The serine/threonine kinase Akt/PKB plays key roles in the regulation of cell growth, survival, and metabolism. It remains unclear, however, whether the functions of individual Akt/PKB isoforms are distinct. To investigate the function of Akt2/PKBβ, mice lacking this isoform were generated. Both male and female Akt2/PKBβ-null mice exhibit mild growth deficiency and an age-dependent loss of adipose tissue or lipoatrophy, with all observed adipose depots dramatically reduced by 22 weeks of age. Akt2/PKBβ-deficient mice are insulin resistant with elevated plasma triglycerides. In addition, Akt2/PKBβ-deficient mice exhibit fed and fasting hyperglycemia, hyperinsulinemia, glucose intolerance, and impaired muscle glucose uptake. In males, insulin resistance progresses to a severe form of diabetes accompanied by pancreatic β cell failure. In contrast, female Akt2/PKBβ-deficient mice remain mildly hyperglycemic and hyperinsulinemic until at least one year of age. Thus, Akt2/PKBβ-deficient mice exhibit growth deficiency similar to that reported previously for mice lacking Akt1/PKBα, indicating that both Akt2/PKBβ and Akt1/PKBα participate in the regulation of growth. The marked hyperglycemia and loss of pancreatic β cells and adipose tissue in Akt2/PKBβ-deficient mice suggest that Akt2/PKBβ plays critical roles in glucose metabolism and the development or maintenance of proper adipose tissue and islet mass for which other Akt/PKB isoforms are unable to fully compensate.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

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Hyperphosphorylation of microtubule-associated proteins such as tau and neurofilament may underlie the cytoskeletal abnormalities and neuronal death seen in several neurodegenerative diseases including Alzheimer's disease. One potential mechanism of microtubule-associated protein hyperphosphorylation is augmented activity of protein kinases known to associate with microtubules, such as cdk5 or GSK3␤. Here we show that tau and neurofilament are hyperphosphorylated in transgenic mice that overexpress human p25, an activator of cdk5. The p25 transgenic mice display silver-positive neurons using the Bielschowsky stain. Disturbances in neuronal cytoskeletal organization are apparent at the ultrastructural level. These changes are localized predominantly to the amygdala, thalamus͞hypothalamus, and cortex. The p25 transgenic mice display increased spontaneous locomotor activity and differences from control in the elevated plus-maze test. The overexpression of an activator of cdk5 in transgenic mice results in increased cdk5 activity that is sufficient to produce hyperphosphorylation of tau and neurofilament as well as cytoskeletal disruptions reminiscent of Alzheimer's disease and other neurodegenerative diseases. Although many protein kinases phosphorylate tau at ADrelevant epitopes in vitro (reviewed in ref.2), only two have been copurified with microtubules, GSK3␤ and cdk5 (3, 4). To our knowledge, only these two kinases will phosphorylate tau in a cellular environment (e.g., refs. 5 and 6). We chose to focus on cdk5 because it is active predominantly in neurons whereas GSK3␤ plays a role in energy metabolism and is active in all cells. cdk5 is a member of the cyclin-dependent protein kinase gene family. Rather than cyclins, cdk5 associates with the positive allosteric regulators p35 (7), amino-terminal proteolytic fragments of p35 (e.g., p25; ref. 8), and p39 (9). These proteins share minimal amino acid sequence homology to cyclins, but the mechanism of activation of cdk5 by p25͞35 may be similar to the activation of cdk2 by cyclin A (10). p25͞35 is expressed predominantly in neurons, implying that most cdk5 activity is concentrated in neuronal structures (7,8). cdk5 plays a pivotal role in neuronal development as evidenced by the abnormal corticogenesis and perinatal lethality of cdk5 knockout mice (11) and the disturbances in neuronal migration and early death in p35 knockout mice (12). A number of potential cdk5 substrates have been identified and most are consistent with a putative role in neurite outgrowth and plasma membrane dynamics. These include cytoskeletal proteins such as tau and neurofilament (e.g., refs. 13 and 14) and synaptic vesicle proteins (15, 16). To clarify the potential role of cdk5 in neurodegenerative diseases in vivo, we overexpressed human p25 in the brains of transgenic mice to determine whether increased cdk5 activity would lead to hyperphosphorylation of tau and neurofilament and͞or cytoskeletal disturbances. Materials and MethodsAnimal Handling. All experimentation was performed under...

Abstract-The ATP-binding cassette transporter A1 (ABCA1) encodes a membrane protein that promotes cholesterol and phospholipid efflux from cells. Mutations in ABCA1 lead to HDL deficiency and tissue accumulation of macrophages in patients with homozygous Tangier disease. In this study, we examined whether the complete absence of ABCA1 or selected inactivation in macrophages is accompanied by an increase in atherosclerotic lesion progression in hypercholesterolemic apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice and LDLR receptor-deficient (LDLr Ϫ/Ϫ ) mice. The absence of ABCA1 led to reduced plasma cholesterol levels in both the apoE Ϫ/Ϫ and LDLr Ϫ/Ϫ mice, along with severe skin xanthomatosis characterized by marked foamy macrophages and cholesterol ester accumulation. However, the complete absence of ABCA1 did not affect the development, progression, or composition of atherosclerotic lesions in either the LDLr Ϫ/Ϫ or the apoE Ϫ/Ϫ mice fed a chow or atherogenic diet. In contrast, bone marrow transplantation studies demonstrated that the selective inactivation of ABCA1 in macrophages markedly increased atherosclerosis and foam cell accumulation in apoE Ϫ/Ϫ . Taken together, these findings demonstrate that the complete absence of ABCA1 has a major impact on plasma lipoprotein homeostasis, and the proposed antiatherogenic effect resulting from ABCA1 deficiency is compensated by a less atherogenic profile. ABCA1 deficiency in macrophages, however, demonstrates the antiatherogenic properties of ABCA1 independent of plasma lipids and HDL levels.

A monoclonal antibody directed against the amino terminal of rat phosphodiesterase 10A (PDE10A) was used to localize PDE10A in multiple central nervous system (CNS) and peripheral tissues from mouse, rat, dog, cynomolgus macaque, and human. PDE10A immunoreactivity is strongly expressed in the CNS of these species with limited expression in peripheral tissues. Within the brain, strong immunoreactivity is present in both neuronal cell bodies and neuropil of the striatum, in striatonigral and striatopallidal white matter tracks, and in the substantia nigra and globus pallidus. Outside the brain, PDE10A immunoreactivity is less intense, and distribution is limited to few tissues such as the testis, epididymal sperm, and enteric ganglia. These data demonstrate that PDE10A is an evolutionarily conserved phosphodiesterase highly expressed in the brain but with restricted distribution in the periphery in multiple mammalian species.